1. Field of the Invention
This invention relates to a process for producing 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide, a valuable intermediate for the synthesis of non-steroidal antiinflammatory agents. More particularly, it relates to the preparation of said carboxylic acid compound by base hydrolysis of alkyl or aralkyl esters of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide and to the use of the acid for production of the antiinflammatory agents N-(2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamid e-1,1-dioxide and N-(2-thiazolyl)-3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxam ide-1,1-dioxide.
2. Description of the Prior Art
The instability of .beta.-keto carboxylic acids, evidenced by their tendency to undergo decarboxylation, is well known to those skilled in the art. U.S. Pat. No. 3,892,740, issued July 1, 1975, and J. Heterocyclic Chem., 13, 333 (1976) report that 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxides have been prepared by hydrolysis of the corresponding ester but they decarboxylate rapidly once formed. The observed instability arises from their .beta.-keto structure.
The preparation of N-substituted-3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dio xides useful as antiinflammatory agents is described in U.S. Pat. Nos. 3,591,584; 3,891,637 and 3,892,740, issued July 6, 1971; June 24, 1975 and July 1, 1975, respectively.
The first patent discloses two routes for the synthesis of N-substituted-benzothiazine-carboxamide-1,1-dioxides: (a) reaction of the appropriate 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-1,1-dioxide with an organic isocyanate; and (b) ammonolysis of an ester of 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide with ammonia or an appropriate amine. The second patent describes the preparation of such compounds wherein the N-substituent is a heterocyclic moiety by a transamidation reaction. The third patent reports preparation of such carboxamide derivatives by contacting a 3,4-dihydro-4-alkoxy- 2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide with a coupling promoter (dicyclohexylcarbodiimide, POCl.sub.3, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) followed by contacting the resulting carboxamide with a mineral acid to convert the 4-alkoxy group to 4-oxo.
In each instance, the particular synthetic route employed carefully avoided the formation of a 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide, even as a transient intermediate, in order to circumvent the heretofore reported instability of the .beta.-keto function of such acids. This reported instability of such acids is in keeping with the well-known tendency of .beta.-keto acids to undergo decarboxylation.